从调节EGFR/ERK1/2通路与Sertoli细胞功能研究淫羊藿总黄酮延缓衰老大鼠睾丸功能衰退机制

With growing number of medium-elderly men of child-bearing, decline in reproductive function caused by increasing age of the male reproductive system has become a hot stop of current research. However, the effective measures for preventing decline in reproductive function with aging are also distressed. It is reported that downregulation of the number and function of Sertoli cells is directly related to declining reproductive function with age, and activation of EGFR/ERK1/2 signal mediated by estrgen/estrgen receptors is a vital pathway to regulation of Sertoli cells function. Our preivous studies showed that total flavonoids of Epimedium increased sperm concentration and sperm motility, delayed decline in reproductive function of aging male rats. Taken together, we speculate total flavonoids of Epimedium might improve declining reproductive function through upregulating the function of Sertoli cells via activation of EGFR/ERK1/2 signal in aging rats. Thus, we first investigate the effects of total flavonoids of Epimedium on Sertoli cells and EGFR/ERK1/2 signal using qPCR, Western blot and immunofluorescence technologies in a naturally aging rat model. Then, treatment the aging rats with estrgen receptors inhibitors, we further determine whether EGFR/ERK1/2 paly a key role in declining reproductive function, and it will provide theoretical and experimental basis of Epimedium total flavonoids for prophylaxis and therapy of declining reproductive function.

随着有生育需求的中老年男性不断增多，因年龄增加所致的生殖功能衰退已引起人们广泛关注，但目前仍缺乏有效的防治措施。已知睾丸Sertoli细胞数量减少和功能下降与男性生殖功能衰退直接相关，而雌激素及其受体调控的EGFR/ERK1/2通路是调节Sertoli细胞增殖和功能的关键途径；我们前期研究显示，淫羊藿总黄酮可提高衰老大鼠睾丸精子浓度和活力，减缓大鼠生殖功能衰退。因此，我们推测淫羊藿总黄酮可能通过调节EGFR/ERK1/2通路与Sertoli细胞功能，进而延缓衰老鼠生殖功能衰退。基于此，本项目首先以自然衰老大鼠为模型，采用qPCR、Western blot、免疫荧光等技术，研究淫羊藿总黄酮对Sertoli细胞和EGFR/ERK1/2通路的影响；随后在雌激素受体阻断的衰老大鼠模型中进一步证实EGFR/ERK1/2通路的作用，为临床应用淫羊藿总黄酮防治睾丸衰老所致生殖功能衰退提供理论和实验依据。

随着有生育需求的中老年男性不断增多，因年龄增加所致的生殖功能衰退已引起人们广泛关注，但目前仍缺乏有效的防治措施。已知睾丸Sertoli细胞数量减少和功能下降与男性生殖功能衰退直接相关，而雌激素及其受体调控的EGFR/ERK1/2通路是调节Sertoli细胞增殖和功能的关键途径；我们前期研究显示，淫羊藿总黄酮可提高衰老大鼠睾丸精子浓度和活力，减缓大鼠生殖功能衰退。因此，我们推测淫羊藿总黄酮可能通过调节EGFR/ERK1/2通路与Sertoli细胞功能，进而延缓衰老鼠生殖功能衰退。因此，本项目首先以自然衰老大鼠为模型，研究了淫羊藿总黄酮对自然衰老大鼠生殖功能衰退的保护作用及分子机制。结果表明，淫羊藿总黄酮可明显提高衰老大鼠睾丸重量及其指数，改善睾丸组织形态，显著提高性激素水平和睾丸组织抗氧化能力，抑制生殖细胞凋亡，从而延缓衰老所致生殖功能衰退，机制可能与提高睾丸组织雌激素受体（ERα和ERβ）表达水平，激活ERK1/2信号通路和改善睾丸Sertoli细胞功能有关。随后，采用自然衰老大鼠模型和D-半乳糖刺激的小鼠睾丸支持细胞系TM4细胞功能衰退模型进一步研究了淫羊藿总黄酮改善Sertoli细胞功能衰退的作用及可能的分子机制。结果表明，淫羊藿总黄酮可显著改善Sertoli细胞的功能，其机制可能与上调IRE1α/XBP1信号通路相关。该项目研究成果将为临床应用淫羊藿总黄酮防治睾丸衰老所致生殖功能衰退提供理论和实验依据。